Formulations Containing Insect Repellent Compounds

ABSTRACT

Dihydronepetalactone, a minor natural constituent of the essential oil of catmints ( Nepeta  spp.) such as  Nepeta cataria , has been identified as an effective insect repellent compound. Synthesis of dihydronepetalactone may be achieved by hydrogenation of nepetalactone, the major constituent of catmint essential oils. This compound, and compositions thereof, which also has fragrance properties, may be used commercially for its insect repellent properties.

This application is a division of, and claims the benefit of the filingdate of, U.S. Ser. No. 11/266,641, filed Nov. 3, 2005, now U.S. Pat. No.8,748,477, which claimed the benefit of U.S. Provisional Application No.60/624,579, filed Nov. 3, 2004, each of which is by this referenceincorporated in its entirety as a part hereof for all purposes.

TECHNICAL FIELD

The present invention relates to the field of insect repellency, and theuse of dihydronepetalactone stereoisomers generally as repellentmaterials.

BACKGROUND

Repellent substances generally cause insects to be driven away from, orto reject, otherwise insect-acceptable food sources or habitats. Mostknown repellents are only mildly toxic. A few of the known repellents,in fact, are not active poisons at all but rather prevent damage toplants/animals or articles of manufacture by making insect food sourcesor living conditions unattractive or offensive. Most current commercialinsect repellents contain the synthetic chemical N,N-diethyl-m-toluamide(DEET) as their primary active ingredient. For instance, repellents soldunder the major commercial brand names such as Off!®, Deep Woods Off!®,and Cutter® are all DEET based products and comprise 85% of insectrepellent sales (Consumer Reports Buying Guide, 1994 Special Year-EndIssue). Further, Consumer Reports tests indicated that products with thehighest concentration of DEET lasted the longest against mosquitoes.

Despite being an effective repellent, however, this compound has certaindrawbacks. Specifically, it possesses an unpleasant odor and imparts agreasy feel to the skin. Although it has recently been re-registered foruse in the US by the EPA, concerns have been raised as to its safety,particularly when applied to children [Briassoulis, G.; Narlioglou, M.;Hatzis, T. (2001) Human & Experimental Toxicology 20(1), 8-14]. Studieshave demonstrated that high concentrations of DEET may give rise toallergic or toxic reactions in some individuals. Other disadvantagesassociated with DEET include that it (1) is a synthetic chemical havinga limited spectrum of activity; (2) is a powerful plasticizer and willdissolve or mar many plastics and painted surfaces; and (3) plasticizesthe inert ingredients typically used in topical formulations in order tolengthen the time of effectiveness. This leads to DEET formulations withlow user acceptability.

As a result of the above limitations, DEET-free products with repellentactivity are finding favor with consumers, and demand for compositionscontaining natural products (versus synthetic chemicals such as DEET) isincreasing. These DEET-free repellent compounds require a combination ofexcellent repellency, high residual activity and relatively little or notoxicity to humans (or pets) and the environment. In response to theseconsumer demands, there is an on-going need to develop new repellentcompounds which can be obtained from, or synthesized from, natural plantmaterials and which are pleasant to use.

Many plant species produce essential oils (aromatic oils) that are usedas natural sources of insect repellent and fragrant chemicals [Hay, R.K. M., Svoboda, K. P., Botany, in “Volatile Oil Crops: their biology,chemistry and production”; Hay, R. K. M., Waterman, P. G. (eds.);Longman Group UK Limited (1993)]. Citronella oil, known for its generalrepellence towards insects, is obtained from the graminaceous plantsCymbopogon winterianus and C. nardus. Examples of plants used as sourcesof fragrant chemicals include Melissa officinalis (Melissa), Perillafrutescens (Perilla), Posostemon cablin (Patchouli) and variousLavandula spp. (Lavender). All of these examples of plants yielding oilof value to the fragrance industry are members of the Labiatae(Lamiaceae) family. Plants of the genus Nepeta (catmints) are alsomembers of this family, and produce an essential oil, which is a minoritem of commerce. This oil is very rich in a class of monoterpenoidcompounds known as iridoids [Inouye, H. Iridoids. Methods in PlantBiochemistry 7:99-143 (1991)], more specifically themethylcyclopentanoid nepetalactones [Clark, L. J. et al. The PlantJournal, 11:1387-1393 (1997)] and derivatives.

Iridoid monoterpenoids have long been known to be effective repellentsto a variety of insect species [Eisner, T. Science 146:1318-1320 (1964);Eisner, T. Science 148:966-968 (1965); Peterson, C. and J. Coats,Pesticide Outlook 12:154-158 (2001); and Peterson, C. et al. Abstractsof Papers American Chemical Society, (2001) 222 (1-2): AGRO73]. U.S.Pat. No. 4,663,346 discloses insect repellants with compositionscontaining bicyclic iridoid lactones (e.g., iridomyrmecin). Further,U.S. Pat. No. 4,869,896 discloses use of these bicyclic iridoid lactonecompositions in potentiated insect repellent mixtures with DEET.

Formal studies concerning the repellency of dihydronepetalactones, aclass of iridoid monoterpenoids derived from nepetalactones (shown inFIG. 1), have been much less conclusive and have failed to teach orimply that these compounds exert a repellent effect on the common insectpests of human society. For example, a study of the composition of thesecretion from anal glands of the ant Iridomyrmex nitidus showed thatisodihydronepetalactone was present in appreciable amounts, togetherwith isoiridomyrmecin [Cavill, G. W. K., and D. V. Clark. J. InsectPhysiol. 13:131-135 (1967)]. Although isoiridomyrmecin was known at thetime to possess good ‘knockdown’ insecticidal activity, no evidence wasprovided in support of a similar activity for isodihydronepetalactone,and no investigation of this compound's repellent effect (as distinctfrom insecticidal activity) was made.

In a later publication by Cavill, G. W. K., et al. [Tetrahedron38:1931-1938 (1982)], the presence of dihydronepetalactones in thedefensive secretion of an ant was again reported, but the authorsconcluded that the compound iridodial, rather than adihydronepetalactone, was the basic repellent constituent.

Most recently, Jefson, M., et al. [J. Chemical Ecology 9:159-180 (1983)]described the repellent effect of dihydronepetalactone. Initialrepellency caused by the undiluted compound was measured with respect tothe ant species Monomorium destructor during feeding. After 25 secondsof exposure to the pure dihydronepetalactone, approximately 50-60% ofthe ants ceased to feed. However, further analyses of the repellencyover a longer time course were not presented, nor were analyses withanything other than the pure undiluted compound. Repellency observedover such short periods of time (seconds) with concentrated chemicals isinsufficient to allow prediction of efficacy in practical applicationssuch as in topical insect repellents.

There is consequently a continuing need for a biologically-basedcompound having improved insect repellent properties (with respect toDEET) and which is substantially non-toxic or only mildly toxic tohumans. Preferred repellents will have activity against a wide varietyof insects, including biting insects, wood-boring insects, noxiousinsects, household pests, and the like. Applicants have found thatdihydronepetalactones, and compositions thereof, perform well as a newclass of effective insect repellent compounds without thedisadvantageous properties characteristic of prior-art compositions.

SUMMARY

One embodiment of this invention is an insect repellent composition orarticle that contains a dihydronepetalactone, or a mixture ofdihydronepetalactone stereoisomers, represented by the general formula:

Another embodiment of this invention is a process for fabricating aninsect repellent composition or an insect repellent article ofmanufacture by providing as the composition or article, or incorporatinginto the composition or article, a dihydronepetalactone, or a mixture ofdihydronepetalactone stereoisomers, as described above.

Yet another embodiment of this invention is the use of adihydronepetalactone, or a mixture of dihydronepetalactonestereoisomers, as described above, or a composition thereof, as aninsect repellent; and thus an embodiment in which, in a method ofrepelling insects, the insects are exposed to a diihydronepetalactone,or a mixture of dihydronepetalactone stereoisomers, or a compositionthereof, as described above.

Yet another embodiment of this invention is a formulated inset repellentcomposition that includes a dihydronepetalactone, or a mixture ofdihydronepetalactone stereoisomers, as described above and one or moreof a carrier, an adjuvant and an additive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemical structures of the naturally-occurring iridoid(methylcyclopentanoid) nepetalactones.

DETAILED DESCRIPTION OF THE INVENTION

A nepetalactone” is a compound having the general structure:

Four chiral centers are present within the methylcyclopentanoid backboneof nepetalactone at carbons 4, 4a, 7 and 7a as shown above;(7S)-nepetalactones are produced by several plants and insects.Dihydronepetalactones are known as minor constituents of the essentialoils of several labiate plants of the genus Nepeta (Regnier, F. E., etal. (1967) Phytochemistry 6:1281-1289; DePooter, H. L., et al. (1988)Flavour and Fragrance Journal 3:155-159; Handjieva, N. V. and S. S.Popov (1996) J. Essential Oil Res. 8:639-643). Dihydronepetalactones aredefined by Formula I:

wherein 1, 5, 6 and 9 indicate the four chiral centers of the moleculeand the structure encompasses all possible stereoisomers ofdihydronepetalactone. The structures of dihydronepetalactonestereoisomers that may be derived from (7S)-nepetalactones are shownbelow.

The term “dihydronepetalactones” or “dihydronepetalactone mixtures”refers to any mixture of dihydronepetalactone stereoisomers. The molaror mass composition of each of these isomers relative to the wholedihydronepetalactone composition can be variable. Dihydronepetalactonesare abbreviated as “DHN”.

A dihydronepetalactone will be understood to encompass any and alldihydronepetalactone stereoisomers and mixtures thereof, unless aparticular isomer or mixture is specified. When dihydronepetalactone isprepared from a naturally occurring source of nepetalactone somevariation in molar concentration of stereoisomers is expected.Preparation from a naturally occurring source is, however, a preferredmethod of preparation.

Dihydronepetalactones are reported in the literature as minorconstituents of the essential oils of several labiate plants of thegenus Nepeta [Regnier, F. E., et al., Phytochemistry 6:1281-1289 (1967);DePooter, H. L., et al., Flavour and Fragrance Journal 3:155-159 (1988);Handjieva, N. V. and S. S. Popov, J. Essential Oil Res. 8:639-643(1996)]. Additionally, dihydronepetalactones have been identified asconstituents of the defensive secretions of certain insects, includingrove beetles [Jefson, M., et al., J. Chem. Ecol. 9:159-180 (1983)] andants, specifically Iridomyrmex species [Cavill, G. W. K. and D. V.Clark. J. Insect Physiol. 13:131-135 (1967)]. In those species thatpossess dihydronepetalactones, it has been proposed that they arebiosynthetically derived from the iridoid monoterpene iridodial.

The chemical synthesis of dihydronepetalactones and their relatediridoid monoterpenoid compounds has been described and found to beconducted in a variety of ways.

The following are useful references relating to synthesis:

-   1) Abelman, M. M. et al. J. Am. Chem. Soc. 104(14):4030-2 (1982)-   2) Fleming, I. and N. K. Terrett. Tetrahedron Lett. 25(44):    5103-5104 (1984); J. Chem. Soc., Perkin Trans. 1:2645-2650 (1998).-   3) Lee, E. and C. H. Yoon. J. Chem. Soc., Chem. Commun. 4: 479-81    (1994).-   4) Nagata, H. and K. Ogasawara. Tetrahedron Lett. 40(36): 6617-6620    (1999).-   5) Nangia, A. et al. Tetrahedron Lett. 35(22): 3755-8 (1994).-   6) Tanimori, S, and M. Nakayama. Agric. Biol. Chem. 55(4): 1181-1184    (1991).-   7) Uyehara, T. et al. J. Chem. Soc., Chem. Commun. 2:113-14 (1989);    Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 32: 441-6 (1990); J.    Org. Chem. 57(11): 3139-3145 (1992).-   8) Wolinsky, J. and E. J. Eustace. J. Org. Chem. 37 (21): 3376-8    (1972).-   9) Wolinsky, J. and D. L. Nelson. Tetrahedron 25(17): 3767-74    (1969).

Regnier et al, op.cit., discloses the preparation of DHN fromnepetalactone by the catalyzed hydrogenation of nepetalactone isolatedfrom the essential oils of plants of the genus Nepeta (catmints). Onepreferred and convenient method for synthesis of dihydronepetalactone isthus by hydrogenation of nepetalactone obtained in relatively pure formfrom the essential oils isolated by various means from plants of thegenus Nepeta (catmints). Catalysts such as platinum oxide and palladiumsupported on strontium carbonate give dihydronepalactone in 24-90%yields (Regnier et al. op.cit.).

The preferred process for producing the dihydronepetalactonesrepresented by Formula I in the present invention, therefore, is byhydrogenation of nepetalactones from plants with oils of definednepetalactone stereoisomer content, an industrially advantageousapproach in terms of production cost and its biological basis. Otherprocesses are as disclosed in U.S. Ser. No. 03/225,290 (WO 03/84946),which is incorporated in its entirety as a part hereof for all purposes.

Methods for isolation or extraction of essential oils include withoutlimitation steam distillation, organic solvent extraction,microwave-assisted organic solvent extraction, supercritical fluidextraction, mechanical extraction and enfleurage (initial coldextraction into fats followed by organic solvent extraction).

The essential oils isolated from different Nepeta species are well knownto possess different proportions of each naturally-occurringstereoisomer of nepetalactone (Regnier et al. op. cit.; DePooter, et al.op.cit.; Handjieva et al op.cit.). Thus DHN prepared from oil derivedfrom any Nepeta species will necessarily be a mixture of stereoisomersthereof, the constitution of that mixture depending upon the particularspecies of Nepeta from which it is derived.

As discussed herein above, four chiral centers are present within themethylcyclopentanoid backbone of the nepetalactone at carbons 4, 4a, 7and 7a as shown:

A total of eight pairs of dihydronepetalactone enantiomers are possibleafter hydrogenation of nepetalactone. Of these, the naturally occurringstereoisomers described thus far are (9S)-dihydronepetalactones.Preferred repellent materials in accordance with the present inventioninclude a mixture of any or all of the possible stereoisomers ofdihydronepetalactone. More preferred repellent materials include amixture of (9S)-dihydronepetalactones. Most preferred are(9S)-dihydronepetalactone stereoisomers derived from(7S)-nepetalactones. This includes the compounds commonly known ascis,trans-nepetalactone, cis,cis-nepetalactone, trans,cis-nepetalactone,and trans,trans-nepetalactone, as illustrated in FIG. 1. The predominantstereoisomers produced by N. cataria (cis,trans and trans,cis-) arepreferred.

Upon completion of the hydrogenation reaction, the resulting mixture ofisomer products may be separated by any conventional method (e.g.,preparative liquid chromatography) to yield each highly purified pair ofdihydronepetalactone diastereomers. This permits the use of variousdifferent diastereomers as are found to be most effective againstparticular insects. It is preferable to isolate a specific nepetalactoneisomer from a plant to convert to its corresponding pair ofdiastereomers by hydrogenation.

In addition to variation in nepetalactone stereoisomer content betweendifferent Nepeta species, intra-species variation is also known toexist. Plants of a given species may produce oils with differentcompositions depending on the conditions of their growth or growth stageat harvest. In fact variation in oil composition independent of growthconditions or growth stage at harvest has been found in Nepeta racemosa,(Clark, L. J., et al. op.cit.). Plants of a single species exhibitingdifferent oil compositions are termed chemotypes. In Nepeta racemosa,chemotypes exhibiting marked differences in the proportion of differentnepetalactone stereoisomers exist. Thus, the preferred process forproducing specific dihydronepetalactone enantiomers is hydrogenation ofan oil from a Nepeta chemotype known to contain specific nepetalactonestereoisomers.

Insects include any member of a large group of invertebrate animalscharacterized, in the adult state (non-adult insect states include larvaand pupa) by division of the body into head, thorax, and abdomen, threepairs of legs, and, often (but not always) two pairs of membranouswings. This definition therefore includes a variety of biting insects(e.g., ants, bees, black flies, chiggers, fleas, green head flies,mosquitoes, stable flies, ticks, wasps), wood-boring insects (e.g.,termites), noxious insects (e.g., houseflies, cockroaches, lice,roaches, wood lice), and household pests (e.g., flour and bean beetles,dust mites, moths, silverfish, weevils).

A host is any plant or animal affected by insects. Typically, hosts areconsidered to be insect-acceptable food sources or insect-acceptablehabitats. An insect susceptible article is any item of commerce createdby man, which is affected by insects. This may include buildings,furniture, and the like. Typically, these articles of manufacture areconsidered to be insect-acceptable food sources or insect-acceptablehabitats.

The terms “insect repellent”, “insect repellent composition” or“repellent composition” will refer to a compound or composition thatdeters insects from their preferred hosts or insect-suitable articles ofmanufacture. Most known repellents are not active poisons at all, butrather prevent damage to plants/animals or articles of manufacture bymaking insect food sources or living conditions unattractive oroffensive. Typically, an insect repellent is a compound or compositionthat can be either topically applied to the host, or is a compound orcomposition that may be incorporated into an insect susceptible articleto produce an insect repellent article that deters insects from thenearby 3-dimensional space in which the host or article exists. Ineither case, the effect of the insect repellent is to drive the insectsaway from or to reject (1) the host, thereby minimizing the frequency ofinsect “bites” to the host; and/or (2) the insect susceptible article,thereby protecting the article from insect damage. Repellents may be inthe form of gases (olfactory), liquids, or solids (gustatory).

Some examples of well-known insect repellents include: benzil; benzylbenzoate; 2,3,4,5-bis(butyl-2-ene)tetrahydrofurfural (MGK Repellent 11);butoxypolypropylene glycol; N-butylacetanilide;normal-butyl-6,6-dimethyl-5,6-dihydro-1,4-pyrone-2-carboxylate(Indalone); dibutyl adipate; dibutyl phthalate; di-normal-butylsuccinate (Tabatrex); N,N-diethyl-meta-toluamide (DEET); dimethylcarbate (endo,endo)-dimethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate); dimethyl phthalate;2-ethyl-2-butyl-1,3-propanediol; 2-ethyl-1,3-hexanediol (Rutgers 612);di-normal-propyl isocinchomeronate (MGK Repellent 326);2-phenylcyclohexanol; p-methane-3,8-diol, and normal-propylN,N-diethylsuccinamate. Standard repellents for mosquitoes, ticks, andthe like are citronella oil (discussed below), dimethyl phthalate,normal-butylmesityl oxide oxalate and 2-ethyl hexanediol-1,3 (See,Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Ed., Vol. 11:724-728; and The Condensed Chemical Dictionary, 8th Ed., p 756).

An insect repellent is any compound or composition that deters insectsfrom a host. It will be appreciated that such usage makes no distinctionamong compounds that have highly ephemeral effects as compared to thosethat exhibit long-term beneficial effects, and/or those that requirevery high surface concentrations before there is an observable effect oninsect behavior.

The term “insect repellent” thus indicates a compound or compositionconferring on a host protection from insects when compared to notreatment at all. Protection desirably results in a statisticallysignificant reduction in numbers of insects, and may, for example, beusefully determined by measuring mean complete protection time (“CPT”)in tests in which insect behavior toward treated animals, includinghumans, and treated inanimate surfaces is observed. Mean CPT refers tothe mean length of time over repetitions of tests in which the timebefore the first landing, probing or biting (in the case of a bitinginsect) or crawling (in the case of a crawling insect such as a tick orchigger) on a treated surface is observed [see e.g. US EPA Office ofPrevention, Pesticides and Toxic Substances product performance testguidelines OPPTS 810.3700; and Fradin, M. S., Day, J. F. (2002) NewEngland Journal of Medicine 347, 13-18]. In one exemplary embodiment ofthis invention, the insect repellent composition hereof has a mean CPTthat is statistically indistinguishable from that of DEET. In the testin which this condition of the respective mean CPT performances of a DHNcomposition and DEET are shown to be statistically indistinguisable, thetest conditions (including amounts of active ingredients) utilized mustof course be identical, or, if not identical, must differ only in waysthat do not prevent utilization of the results for the purposes ofdocumenting the existence of the condition described.

As noted above, DHN compares favorably in performance with DEET.Moreover, DHN is advantageously prepared from naturally occurringnepetalactone derived from plants whereas DEET, and many other insectrepellents, are not prepared from natural sources—an important consumerconsideration when choosing an effective repellent. Preparation fromnatural sources also offers the potential for low production costs.

A useful property of DHN is that it provides a considerable improvementover the odor of DEET while exhibiting effective insect repellency. TheDHN compounds and compositions of this invention possess a pleasantfragrance. The fragrance notes of the DHN materials make them useful inimparting, altering, augmenting or enhancing the overall olfactorycomponent of an insect repellent composition or article, for example, byutilizing or moderating the olfactory reaction contributed by one ormore other ingredients in the composition. Specifically, the DHNcompositions of the invention may be utilized to either mask or modifythe odor contributed by other ingredients in the formulation of thefinal repellent composition or article, and/or to enhance consumerappeal of a product by imparting a characteristic perfume or aroma.

In addition to the chemical compounds and compositions as describedabove, a variety of effective insect repellents contain essential oilsand/or active ingredients of essential oils. “Essential oils” aredefined as any class of volatile oils obtained from plants possessingthe odor and other characteristic properties of the plant. Examples ofrepellent compounds that are essential oils include: almond bitter oil,anise oil, basil oil, bay oil, caraway oil, cardamom oil, cedar oil,celery oil, chamomile oil, cinnamon oil, citronella oil, clove oil,coriander oil, cumin oil, dill oil, eucalyptus oil, fennel oil, gingeroil, grapefruit oil, lemon oil, lime oil, mint oil, parsley oil,peppermint oil, pepper oil, rose oil, spearmint oil (menthol), sweetorange oil, thyme oil, turmeric oil, and oil of wintergreen. Examples ofactive ingredients in essential oils are: citronellal, methylsalicylate, ethyl salicylate, propyl salicylate, citronellol, safrole,and limonene.

In contrast to an insect repellent, an insecticide is a compound ormixture that is capable of poisoning an insect via its oral ingestion,by contact with the insect cuticle, or by fumigant action through theair. Thus, an insecticide is a type of pesticide designed to controlinsect life that is harmful to man (i.e., directly harmful as diseasevectors, or indirectly harmful by destruction of crops, food products,or textile fabrics). Several well-known insecticides include: inorganiccompounds (such as arsenic, lead and copper); naturally occurringorganic compounds (such as rotenone, pyrethrins, nicotine, coppernaphthenate and petroleum derivatives); and synthetic organic compounds(such as DDT, dieldrin, endrin, chlordane, lindane, para-dichlorobenzeneand parathion).

A potentiated insect repellent composition is a repellent compositionthat produces a result substantially in excess of that which reasonablycould be expected or predicted from the known effect of the componentseither alone or additively. In the present invention, a potentiatedinsect repellent composition will typically includedihydronepetalactones or a mixture thereof, and at least one otherinsect repellent compound that is not itself dihydronepetalactone(sometimes referred to as a non-dihydronepetalactone insect repellentcompound).

An insect repellent composition can be used as a component of an insectrepellent article, wherein an insect repellent article is an article ofmanufacture possessing insect repellency that is enhanced, altered, oraugmented by the presence thereon or therein of an insect repellentcomposition. As used herein with respect to insect repellency, the terms“alter” and “modify” in their various forms refer to a means ofsupplying or imparting insect repellency to a composition, or augmentingthe existing insect repellency characteristics where natural repellencyis deficient in some regard, or supplementing the existing insectrepellency to modify its quality, or character. The term “enhance” isintended to mean the intensification (without effecting a change in kindor quality of repellency) of one or more repellency properties in aninsect repellent composition or insect repellent article.

The dihydronepetalactones of the present invention possess uniqueproperties of insect repellency and are particularly effective against awide spectra of common insect pests, including biting insects,wood-boring insects, noxious insects, and household-pests, and otherinsects that interfere with human society. These insects include avariety of biting insects (e.g., ants, bees, black flies, chiggers,fleas, green head flies, mosquitoes, stable flies, ticks, wasps, hornflies), wood-boring insects (e.g., termites), noxious insects (e.g.,houseflies, cockroaches, lice, roaches, wood lice), and household pests(e.g., flour and bean beetles, dust mites, moths, silverfish, weevils).In the case of mosquitoes, which convey pathogenic microbes, theserepellent properties are additionally effective for preventing infectionwith such diseases.

One property that is important to overall insect repellency is surfaceactivity, as most (if not all) repellents contain both polar andnon-polar regions in their structure. A second property is volatility.

Insect repellents form an unusual class of compounds where evaporationof the active ingredient from the host's skin surface or from the insectrepellent article is necessary for effectiveness, as measured by thehost's protection from insect bites or the article's protection frominsect damage. In the case of a topical insect repellent, a certainminimum concentration of repellent is needed in the air space directlyabove the skin surface of the host in order to repel insects, and thisconcentration is a measure of the potency of the repellent. However,evaporation rate is also affected by the rate of skin absorption—in mostcases, penetration into and through the skin is an undesirable mode ofloss of compound from the skin surface. Similar considerations must bemade for insect repellent articles, concerning the minimum concentrationof repellent required in the three-dimensional air space surrounding thearticle itself.

A variety of strategies are available to researchers attempting tobalance these properties of evaporation (and, optionally, penetration).First, it is possible to find a single active ingredient having theright balance of physical properties. Alternatively, the activeingredient could be formulated with polymers and inert ingredients addedto the active ingredient for the purpose of modifying the persistence ofthe active ingredient on the host's skin surface or within the insectrepellent article. However, adding inert ingredients to the activeingredient limits the number of molecules of active ingredient on thesurface of the repellent film or article. Since a molecule must be onthe surface in order to evaporate, the evaporation rate is lowered. Thiscarries with it the negative consequence of diluting the concentrationof active ingredient that can be applied to the host's skin surface orthat is present on the surface of an insect repellent article. This, inturn, reduces the overall potency of a formulation containing inertingredients. In a third alternative, the active ingredient can becontained in microcapsules to control rates of loss from the host's skinsurface or insect repellent article. Finally, another technique oflimiting the evaporation rate of active ingredient is to synthesize aprecursor molecule, which slowly disintegrates on the skin surface orinsect repellent article to release the active ingredient.

For example, release of the active ingredient may be, for example, bysub-micron encapsulation, in which the active ingredient is encapsulated(surrounded) within a skin nourishing protein just the way air iscaptured within a balloon. The protein may be used at, for example, a20% concentration. An application of repellent contains many of theseprotein capsules that are suspended in either a water-based lotion, orwater for spray application. After contact with skin the proteincapsules begin to breakdown releasing the encapsulateddihydronepetalactone. The process continues as each microscopic capsuleis depleted then replaced in succession by a new capsule that contactsthe skin and releases its active ingredient. The process may take up to24 hours for one application. Because protein's adherence to the skin isso effective, these formulas are very resistant to perspiration(sweat-off), and water. When applied they are dry and comfortable withno greasiness. This system results in very effective protection, but itis only effective when used on skin because clothing does not have thecapability to release the proteins. An alternative system uses a polymerto encase the repellent, which slows down early evaporation leaving moredihydronepetalactone available for later evaporation. This system canoften increase a repellent's length of effectiveness by 25% to 50% overcomparable non-entrapped products, but often feels greasy because of thepresence of the polymer. In another alternative, a synergist is used tokeep stimulating the evaporation of the dihydronepetalactone in thecomposition.

Regardless of the particular strategy applied to control volatility ofan insect repellent, each repellent must have a minimum effectiveevaporation rate (MEER) from the skin surface or insect repellentarticle to maintain the necessary minimum concentration of repellent inthe air space directly above the skin surface/article for effectiveinsect repellency. An evaporation rate greater than the minimumeffective evaporation rate (MEER) results in a significant andundesirable mode of loss. The issue is further complicated, however,since the MEER will change as a function of conditions in the field.Both the avidity or biting tendency of an insect and the concentrationof insects in the host's environment must be considered. For example, asthe avidity of mosquitoes increases, a higher MEER will be required. Inan environment having a low concentration of mosquitoes where thosemosquitoes are not hungry, the MEER could be as low as 2, or morecommonly, 5 or 6. In contrast, in an environment having a highconcentration of hungry mosquitoes, the MEER might be as high as 12-15.Preferred in the present invention are insect compositions wherein theskin surface evaporation rate is at least equal to a minimum effectiveevaporation rate over a period of time where a preferred period of timeis about 5 hours.

The effectiveness of DHN or any insect repellent depends upon thesurface concentration of the active ingredient on the host surface towhich it is applied. Many compounds known in the art to exhibit insectrepellency do so, however, only in relatively concentrated form. See,for example, McGovern et al in U.S. Pat. No. 4,416,881, which disclosesthe use of repellent concentrations of 6.25-25%. In other situationsrepresentative of the art, it is often found that concentrations of DEETmuch below 1% require repeated application to achieve an effectivesurface concentration, yet concentrations above 30% result in excessivesurface concentration, which is both wasteful and conducive to theproduction of undesirable side effects. A further advantage of thisinvention is consequently that DHN not only provides effective insectrepellency at concentrations similar to those employed for DEET, DHN maybe employed at concentrations up to and including neat DHN (i.e. thecomposition hereof may, if desired, contain 100% by weight DHN). Theproperty of effective repellency in DHN provides many options foreconomical utilization of the DHN active ingredient over a wide range oflevels of concentration.

In one embodiment of this invention, DHN is incorporated in effectiveamounts into a composition suitable for application to a host plant oranimal, preferably to human skin. Suitable compositions include DHN anda vehicle or a carrier, preferably an alcohol such as iso-propylalcohol, a lotion such as one of the numerous skin creams known in theart, or a silicaceous clay. Preferably the DHN is present in the insectrepellent composition of the invention at a concentration of about 0.1%to 30% by weight, preferably about 0.5% to 20% by weight, and mostpreferably about 1% to 15% by weight.

In this invention, a variety of carriers or diluents for theabove-disclosed dihydronepetalactones can be used. The carrier allowsthe formulation to be adjusted to an effective concentration ofrepellant molecules. When formulating a topical insect repellent,preferably, the repellant molecules are mixed in a dermatologicallyacceptable carrier. The carrier may further provide water repellency,prevent skin irritation, and/or soothe and condition skin. Factors toconsider when selecting a carrier(s) for any formulation of insectrepellent include commercial availability, cost, repellency, evaporationrate, odor, and stability. Some carriers can themselves have repellentproperties.

For the present invention, the specific choice of a carrier, if any, tobe utilized in achieving the desired intimate admixture with the finalproduct can be any carrier conventionally used in insect repellentformulations. The carrier, moreover, should preferably also be one thatwill not be harmful to the environment. Accordingly, the carrier can beany one of a variety of commercially available organic and inorganicliquid, solid, or semi-solid carriers or carrier formulations usable informulating insect repellent products. For example the carrier mayinclude silicone, petrolatum, lanolin or many of several other wellknown carrier components.

Examples of organic liquid carriers include liquid aliphatichydrocarbons (e.g., pentane, hexane, heptane, nonane, decane and theiranalogs) and liquid aromatic hydrocarbons. Examples of other liquidhydrocarbons include oils produced by the distillation of coal and thedistillation of various types and grades of petrochemical stocks,including kerosene oils which are obtained by fractional distillation ofpetroleum. Other petroleum oils include those generally referred to asagricultural spray oils (e.g., the so-called light and medium sprayoils, consisting of middle fractions in the distillation of petroleumand which are only slightly volatile). Such oils are usually highlyrefined and may contain only minute amounts of unsaturated compounds.Such oils, moreover, are generally paraffin oils and accordingly can beemulsified with water and an emulsifier, diluted to lowerconcentrations, and used as sprays. Tall oils, obtained from sulfatedigestion of wood pulp, like the paraffin oils, can similarly be used.Other organic liquid carriers can include liquid terpene hydrocarbonsand terpene alcohols such as alpha-pinene, dipentene, terpineol, and thelike.

Other carriers include silicone, petrolatum, lanolin, liquidhydrocarbons, agricultural spray oils, paraffin oil, tall oils, liquidterpene hydrocarbons and terpene alcohols, aliphatic and aromaticalcohols, esters, aldehydes, ketones, mineral oil, higher alcohols,finely divided organic and inorganic solid materials.

Still other liquid carriers can include organic solvents such asaliphatic and aromatic alcohols, esters, aldehydes, and ketones.Aliphatic monohydric alcohols include methyl, ethyl, normal-propyl,isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohols. Suitablealcohols include glycols (such as ethylene and propylene glycol) andpinacols. Suitable polyhydroxy alcohols include glycerol, arabitol,erythritol, sorbitol, and the like. Finally, suitable cyclic alcoholsinclude cyclopentyl and cyclohexyl alcohols.

Conventional aromatic and aliphatic esters, aldehydes and ketones can beused as carriers, and occasionally are used in combination with theabove-mentioned alcohols. Still other liquid carriers include relativelyhigh-boiling petroleum products such as mineral oil and higher alcohols(such as cetyl alcohol). Additionally, conventional or so-called“stabilizers” (e.g., tert-butyl sulfinyl dimethyl dithiocarbonate) canbe used in conjunction with, or as a component of, the carrier orcarriers comprising the compositions of this invention.

Solid carriers which can be used in the compositions of the presentinvention include finely divided organic and inorganic solid materials.Suitable finely divided solid inorganic carriers include siliceousminerals such as synthetic and natural clay, bentonite, attapulgite,fuller's earth, diatomaceous earth, kaolin, mica, talc, finely dividedquartz, and the like, as well as synthetically prepared siliceousmaterials, such as silica aerogels and precipitated and fume silicas.

Examples of finely divided solid organic materials include cellulose,sawdust, synthetic organic polymers, and the like. Examples ofsemi-solid or colloidal carriers include waxy solids, gels (such aspetroleum jelly), lanolin, and the like, and mixtures of well-knownliquid and solid substances which can provide semi-solid carrierproducts, for providing effective repellency within the scope of theinstant invention.

Other carriers suitable for use in a composition of this invention, inaddition to water, include one or more of the following:

Acetone

C10˜C18 Triglycerides

C12˜C18 Acid Triglycerides

Dipropyl, Dibutyl, Diisocetyl, Diisopropyl or Dimethyl Oxalate

Cyclo(ethoxy)methicone

Amyl, Methyl, Butyl, Ethyl, Ethoxyethanol, Ethoxydiglycol orTetrahydrofurfuryl Acetate

Ethoxydiglycol

Kerosene

Ethoxyethanol

Diacetin

Benzyl, Diacetone, Denatured ethyl, Tetrahydrofurfuryl or Oleyl Alcohol

Benzyl Benzoate or Laurate

Ethylene Carbonate

Ethyl Hexanediol

Oil of Bertholetta Excelsa Nut, Carthamus Tinctorius, Helianthus Annuus,Ricinus Communis, Aleurites Moluccana, Linum Usitatissimum, CocosNucifera, Zea Mays, Pinus Palustris, Sesamum Indicum, Glycine Soja,Helianthus Annuus, Prunus Amygdalus Dulcis, Olea Europaea, ElaeisGuineensis, Prunus Persica Kernel, Cucurbita Pepo, Brassica Campestris,Oryza Sativa, Oryza Saliva, Carthamus Tinctorius, Juglans Regia orTriicum Vulgare

Dibutyl Phthalate or Sebacate

Furfural

Butoxy-diglycol, -propanol or -ethanol

Diethoxyethyl Succinate

Diethyl Oxalate, Phthalate, Sebacate or Succinate

n- or t-Butyl, Hexyl or Isopropyl Alcohol

Glycofurol

Gycol

Butylene, Hexylene, Diethylene, Dipropylene, Pentylene, Propylene orTriethylene Glycol

C6˜C20 linear, branched or cyclic alkane, alkanol or alkane polyol

Butyloctanol

Dihexyl, Diisobutyl, Diisodecyl, Ditridecyl, Dibutyl, Diisocetyl,Diisopropyl, Dipropyl or Diisoponyl Adipate

Butyrolactone

1,2,6-Hexanedol

Caprylic, Capric, Lauric or Stearic Triglyceride

Isoamyl, Isobutyl, Isopropy or Propyl Acetate

Isobutoxypropanol

Diisopropyl Sebacate

Dimethoxydiglycol

Isobutyl, Methyl or Stearyl Benzoate

Isopropyl Laurate, Myristate, Palmitate or Stearate

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate

Dimethyl Phthalate, Glutarate, Maleate, Adipate or Succinate

Dimethyl Sulfone

Dimethyl Ether

Dimethyl Isosorbide

Dioctyl Sebacate, Adipale, Phthalate or Succinate

Methylethylketone

3-Methoxybutanol

Dipentene

Methoxydigycol

Diphenyl Methane

Methoxy-ethanol, -isopropanol or -methylbutanol

C4˜C400 polyethylene, polypropylene, polyethylene/ether orpolypropylene/ether glycol

Perfluorodecalin

Methylal

Perfluorotetralin

Pheroxyisopropanol

Phenylpropanol

Methyl Hexyl Ether

Methylpropanediol

Methyl Pyrrolidone

Methyl Butyl Ketone

Thiolanediol

Toluene

Propanediol

Triacetin

Tributyl Citrate

Tributylcresylbutane

Propylene Carbonate

Tricaprin

Tricaprylin

Trichloroethane

Triheptanoin

Trihydroxystearin

Triisononanoin

Tiisostearin

Trilaurin

Trilinolein

Trilinolenin

Trimethylhexanol

Trimyristin

Trioctanoin

Triolein

Tripalmitin

Trisebacin

Tristearin

Triundecanoin

Xytene

In addition to the above-mentioned materials, such as the liquidhydrocarbons, the carrier can contain conventional emulsifying agentswhich can be used for causing the dihydronepetalactone compounds to bedispersed in, and diluted with, water for end-use application.

Insect repellent compositions of the present invention containing thedihydronepetalactones may also contain adjuvants known in the art ofpersonal care product formulations, such as thickeners, bufferingagents, chelating agents, preservatives, fragrances, antioxidants,gelling agents, stabilizers, surfactants, emolients, coloring agents,aloe vera, waxes, other penetration enhancers and mixtures thereof, andtherapeutically or cosmetically active agents.

Additionally, the compositions of the present invention may also containother adjuvants such as one or more therapeutically or cosmeticallyactive ingredients. Exemplary therapeutic or cosmetically activeingredients useful in the compositions of the invention includefungicides, sunscreening agents, sunblocking agents, vitamins, tanningagents, plant extracts, anti-inflammatory agents, anti-oxidants, radicalscavenging agents, retinoids, alpha-hydroxy acids, emollients,antiseptics, antibiotics, antibacterial agents or antihistamines, andmay be present in an amount effective for achieving the therapeutic orcosmetic result desired.

Additionally, the compositions of this invention may contain one or moreother additives such as an antioxidant, an emulsion stabilizer, apreservative, a propellant, an emollient, a sunscreen agent, asurfactant, an emulsifying agent, a solubilizing agent and/or anultraviolet light absorber. Examples of materials that may function assuch additives are set forth below.

The compositions of this invention may include one or more materialsthat may function as an antioxidant, such as reducing agents and freeradical scavengers. Suitable materials that may function as anantioxidant include one or more of the following:

Acetyl Cysteine

Ascorbic Acid

Ascorbyl Palmitate or Stearate

t-Butyl Hydroquinone

Cysteine

Diamylhydroquinone

Dicetyl, Dilauryl, Dimyristyl, Distearyl or Ditridecyl Thiodipropionate

Erythorbic Acid

2-Ethylhexyl, Lauryl, Myristyl, Palmitoyl or Stearyl 4-methoxycinnamate

Ethyl Ferulate

Ferulic Acid

Hydroquinone

p-Hydroxyanisole

Hydroxylamine Sulfate

Magnesium Ascorbate

Magnesium Ascorbyl Phosphate

Octyl Gallate

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate

Octocrylene

Phloroglucinol

Polyethylene glycol ether of tocopherol

Potassium Ascorbyl Tocopheryl Phosphate

Potassium Sulfite

Propyl Gallate

Rutin

Sodium Ascorbate

Sodium Erythorbate

Sodium Sulfite

Sodium Thloglycolate

Sorbityl Furfural

Tertiary butyl 4-methoxy phenol

Thiodiglycol

Thiodiglycolamide

Thioglycolic Acid

Thiolactic Acid

Thiosalicylic Acid

Tocopherol

Tocopheryl Acetate

Tocopheryl Linoleate

Tocopheryl Nicotinate

Tocopheryl Succinate

Tris(Nonylphenyl)Phosphite

The compositions of this invention may also include one or morematerials that may function as an emulsion stabilizer. These materialswould not act as primary emulsifiers, but would prevent or reduce thecoalescence of emulsified droplets. This could be accomplished, forexample, by modifying the continuous or the disperse phase of theemulsion through electrical repulsion, from changes in viscosity, orfrom film formation on the droplet surface. Suitable materials that mayfunction as an emulsion stabilizer include one or more of the following:

Cetyl Alcohol

Montmorillonite

Aluminum Caprylate, Stearate, Laurate, Palmitate, Lanolate or Myristate

C₁₅˜C₁₈ Glycol

Dodecylhexadecanol

H(OCH₂CH₂)_(n)OH where n=350 to 160,000

Pectin

Glucose Pentaacetate

Glycol Oleate, Palmitate, Stearate or Ricinoleate

(Alkyl) cellulose

Hydroxyalkyl (alkyl) cellulose

Calcium Laurate, Myristate or Stearate

C₁₀˜C₅₀ alcohol such as cetyl, myristyl, stearyl, tallow or laurylalcohol

Polyvinyl Acetate

Lanolin

Styrene/maleic anhydride copolymer

Xanthan gum

The compositions of this invention may also include one or morematerials that may function as a preservative, which would prevent orretard microbial growth and thus protect the composition (or productsmade therefrom) from spoilage or from inadvertent contamination by theconsumer during use. Suitable materials that may function as apreservative include one or more of the following:

Ammonium Benzoate or Propionate

Chloroxy enol

Isobutylparaben

o, m or p-Cresol

Isodecylparaben

Benzoic Acid

Isopropyl Cresol, Paraben or Sorbate

Benzotriazole

Benzyl Alcohol

Magnesium Benzoate

Benzylparaben

Dehydroacetic Acid

Magnesium Propionate

5-Bromo-5-Nitro-1,3-Dioxane

Diazolidinyl Urea

Magnesium Salicylale

2-Bromo-2-Nitropropane-1,3-Diol

Dibromopropamidine Diisothionate

Butyl Benzoate

Dimethyl Hydroxymethyl Pyrazole

Butylparaben

Dimethylol Ethylene Thiourea

Calcium Benzoate, Salicylate, Sorbate, Paraben or Propionate

Dimethyl Oxazolidine

Methyl Hydroxyl Hydantoin

Methyldibromo Glutaronitrile

Methylisothiazolinone

Methylparaben

Ethylparaben

Chlorhexidine Diacetate, Digluconate or Dihydrochloride

Formaldehyde

Glutaral

Glyoxal

Chloroacetamide

Hexamidine

Chlorobutanol

Hexamidine Diparaben

Phenol

p-Chloro-m-Cresol

Hexamidine Paraben

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate

Octocrylene

Phenoxyethanol

Chlorophene

4Hydroxybenzoic Acid

Phenoxyethylparaben

P-Chlorophenol

Hydroxymethyl Dioxoazabicyclooctane

Phenoxyisopropanol

Chlorothymol

Imidazolidinyl Urea

Phenyl Benzoate

Phenyl Mercuric Acetate, Benzoate, Borate, Bromide or Chloride

Potassium Salicylate, Sorbate, Benzoate, Propylparaben, Butylparaben,Ethylparaben, Methylparaben, Paraben, Phenoxide, o-Phenylphenate or

Propionate

Propionic Acid

Propyl Benzoate

Phenylparaben

Propylparaben

o-Phenylphenol.

Silver Borosilicate

Silver Magnesium Aluminum Phosphate

Sorbic Acid

Sodium Hydroxymethylglycinate, Methylparaben, Paraben, Phenolsulfonate,Phenoxide, o-Phenylphenate, Propionate, Propylparaben, Pyrithione,Salicylate, Sorbate, Benzoate, Butylparaben, p-Chloro-m-Cresol,Dehydroacetate, Ethylparaben, Formate or Hydroxymethane Sulfonate

Zinc Pyrithione

The compositions of this invention may also include one or morematerials that may function as a propellant, which are chemicals usedfor expelling products from pressurized containers (aerosols). Thefunctionality of a propellant depends on its vapor pressure at ambienttemperature and its compressibility. Liquids or gases can be used aspropellants as long as the pressure developed within the container issafely below the container's bursting pressure under normal storage anduse conditions.

Suitable materials that may function as a propellant include one or moreof the following:

Butane

CH₃CClF₂

Nitrogen

Carbon Dioxide

CH₃CF₂

Nitrous Oxide

Dimethyl Ether

Isobutane

Pentane

Ethane

Isopentane

Propane

CH₃CHF₂

The compositions of this invention may also include one or morematerials that may function as an emollient, which is a cosmeticingredient that maintains the soft, smooth, and pliable appearance ofskin. The purpose of an emollient is to remain on the skin surface or inthe stratum corneum to act as a lubricant, to reduce flaking, and toimprove the skin's appearance. Suitable materials that may function asan emollient include one or more of the following:

Acetylated Lanolin or Lanolin Alcohol

Bisphenylhexamethicone

Bertholetta Excelsa Nut Oil

Caprylic/Capric Glycerides

Butoxyethyl Stearate

Caprylic/Capric/Succinic Triglyceride

Acetylated Sucrose Distearate

Acetyl Trihexyl Citrate

Butyl Isostearate, Myristate, Oleate or Stearate

Caprylyl Glycol

Acetyl Trioctyl Citrate

Cetearyl Octanoate or Palmitate

Prunus Armenlaca Kernel Oil

Cetyl Acetate, Caprylate, Lactate, Laurate, Octanoate or Oleate

Arachidyl Propionate

C14˜C15 Alcohols

Cetylarachidol

Argania Spinosa Oil

C12˜C28 Alkyl Acetate, Benzoate or Lactate or Octanoate

Persea Gratissima Oil

Orbignya Olelfera Oil

Melissa Officinalis Seed Oil

C24˜C28 Alkyl Methicone

C12˜C13 Alkyl Octanoate

Cetyl Glycol, Glycol Isostearate or Glycol Palmitate

Benzyl Laurate

Bis-Diglyceryl Polyacyladipate-1 or -2

Camellia Kissi Oil

Isostearyl, Myristyl, Lauryl, Isocetyl, Pentadecyl, Oleyl, Tridecyl orUndecyl Alcohol

Isostearyl Glyceryl Ether

Isostearyl Benzoate, Lactate, Neopentanoate, Octanoate, Palmitate orMyristate

Methyl Stearate

Rosa Moschata Seed Oil

Hydroxycetylisostearate

Isatis Tinctoria Oil

Isoamyl Laurate

Isobutyl Myristate, Palmitate, Pelargonate or Stearate

Isopropyl Laurate, Myristate, Palmitate or Stearate

Isotridecyl Isononanoate

Myristyl Isostearate, Lactate, Neopentanoate, Octanoate or Propionate

Actinidia Chinensis Seed Oil

Isocetyl Isodecanoate, Palmitate or Stearate

Lanolin

Lanolin Oil or Wax

Isodecyl Citrate, Hydroxystearate, Laurate, Myristate, Neopentanoate,Palmitate or Stearate

Neopentyl Glycol Dicaprylate, Dicaprate, Dilaurate or Dioctanoate

Nonyl Acetate

Lauryl Glycol

Octyl Acetoxystearate

Lauryl Isostearate or Lactate

Octyldecanol

Octyldodecanol

Octyldodecyl Benzoate, Lactate, Neopentanoate or Octanoate

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate Isohexadecane

Methyl Benzoate, Caproate, Caprylate, Caprate or Glucose Dioleate

Isohexyl Neopentanoate, Palmitate or Laurate

Octyl Hydroxystearate, Laurate, Isopalmitate, Isostearate, Myristate,Neopentanoate, Oleate, Palmitate or Stearate

Methyl Glucose Isostearate, Laurate, Sesquicaprylate, Sesquicaprate,Sesquilaurate or Sesquistearate

Isopropyl Hydroxycetyl Ether

Isopropyl Hydroxystearate, Isostearate, Lanolate, Laurate, Linoleate,Myristate or Oleate

2-Oleamido-1,3-Octadecanediol

Oleyl Acetate, Lactate or Oleate

Methyl Hydroxystearate, Laurate, Isostearate, Myristate, Oleate,Palmitate or Pelargonate

Isopropyl Palmitate, Isopropyl or Stearate

Isosorbide Laurate

Passiflora Eduls Oil

Polyethyelene Glycol Glycerides

Polyglyceryl Myristate, Oleate, Pentastearate or Ricinoleate

Polyglyceryl Oleyl Ether

Polyethylene Glycol Tricapryl Citrate, Tricetyl Citrate, TrilaurylCitrate, Trimyristyl Citrate or Tristearyl Citrate

Polyethylene Glycol Castor Oil

Pentaerythrityl Dioleate, Distearate, Stearate, Tetrabenzoate orTrioleate

Polyglyceryl Sesquioleate, Stearate, Tetraoleate, Tetrastearate,Caprate, Caprylate, Decalinoleate, Laurate or Isopalmitate

Propylene Glycol Hydroxystearate Stearate, Laurate, Linoleate,Myristate, Ricinoleate, Stearte, Oleate, Soyate or Caprylate

Propylene Glycol Myristyl Ether or Myristyl Ether Acetate

Sucrose Polyoleate, Polypalmate, Polystearate, Ricinoleate, Stearate,Triacetate, Polylaurate, Polylinoleate, Myristate, Oleate, Laurate orPalmitate

Polypropylene Glycol Lauryl, Cetyl, Stearyl, Oleyl or PentaerythritylEther

Tridecyl Neopentanoate, Octanoate, Stearate or Isononanoate

Stearyl Acetate, Benzoate or Lactate

Stearyl Glycol Isostearate or Citrate

Polypropylene Glycol/Polyethylene Glycol

Trimethylolpropane or Propene

Trioctyl Trimellitate

Tris(Tributoxysiloxy)Methylsilane

The compositions of this invention may also include one or morematerials that may function as as a sunscreen agent. Under 58 Fed. Reg.28194 (May 12, 1993), a sunscreen active ingredient is defined as an“ingredient that absorbs at least 85 percent of the radiation in the UVrange at wavelengths from 290 to 320 nanometers, but may or may nottransmit radiation at wavelengths longer than 320 nanometers.” Suitablematerials that may function as a sunscreen agent include one or more ofthe following:

Aminobenzoic Acid (“PABA”)

Glyceryl Aminobenzoate (Glyceryl PABA)

(Dxybenzone (Benzophenone-3)

Cinoxate

Homosalate

Gctyl Dimethyl PABA

Diethanolamine Methoxycinnamate

2-Ethylhexyl, Lauryl, Myristyl, Palmitoyl, or Stearyl 4-methoxycinnamate

Lawsone with Dihydroxyacetone

Phenylbenzimidazole Sulfonic Acid

Menthyl Anthranilate

Red Petrolatum

Digalloyl Trioleate

Gctocrylene

Sulisobenzone (Benzophenone-4)

Dioxybenzone (Benzophenone-8)

Octyl Methoxycinnamate

Titanium Dioxide

Ethyl 4-[bis(Hydroxypropyl)] Aminobenzoate (Ethyl Dihydroxypropyl PABA)

Octyl Salicylate

Trolamine Salicylate

The compositions of this invention may also include one or morematerials that may function as as a surfactant, an emulsifying agent ora solubilizing agent. Such a material may be used to reduce surfacetension, to form complex films on the surface of emulsified droplets, tocreate a repulsive barrier on emulsified droplets to prevent theircoalescence, to retard physical changes in emulsions throughout duringshelf-life or to cause a solute to become part of a micelle formed by asurfactant. Suitable materials that may function as a surfactant, anemulsifying agent or a solubilizing agent include one or more of thefollowing:

C50˜C650 linear or branched dihydroxy polyoxyethylene/polyoxypropyleneblock copolymer

C50˜C650 branched polyhydroxy polyoxyethylene/polyoxypropylene blockcopolymer of ethylene diamine

C12˜C330 ethoxylated alkyl phenol

C16˜C140 polyethylene glycol ether of C12˜C₆₀ alcohols

Carboxylic acid esters of C12˜C330 ethoxylated alkyl phenol

Ester of C12˜C40 Carboxlic Acid and C8˜C40 Polyethylene Glycol

Ester of Caprylic or Capric Triglyceride and C8˜C40 Polyethylene Glycol

Phosphoric acid esters of C12˜C330 ethoxylated alkyl phenol

Phosphoric acid esters and diesters of C16˜C140 polyethylene glycolether of C₁₂˜C₆₀ alcohols

Abietic Acid

Calcium Stearoyl Lactylate

Cetethyl Morpholinium Ethosutfate

Cetrimonium Bromide, Chloride, Methosulfate or Tosylate

Cetyl Alcohol

Cetyl Dimethicone Copolyol

Cetyl Glyceryl Ether/Glycerin Copolymer

Cetyl Phosphate

Cetearyl Glucoside

Dextrin Behenate, Laurate, Myristate, Palmitate or Stearate

Dicetyl Phosphate

Diethylaminoethyl Laurate or Stearate

Dimethyl Octynediol

Dimyristyl Phosphate

Glyceryl Arachidate, Behenate, Caprylate, Caprate, Cocoate, Erucate,Hydrogenated Rosinate, Hydroxystearate, Isopalmitate, Isostearate,Isotridecanoate/Stearate/Adipate, Lanolate, Laurate, Oleate, Linoleate,Linolenate, Oleate, Montanate, Myristate, Palmitate, Stearate,Palmitoleate, Ricinoleate or Uridecylenate

Glycol Octanoate

Hydrogenated Lecithin

Hydrogenated Palm Glyceride

Hydroxycetyl Phosphate

Hydroxyethyl Glyceryl Oleate and/or Stearate

Lanolin

Laurtrimonium Chloride

Lauryl Phosphate

Lecithin

Mannitan Laurate or Oleate

Myristoyl Methylalanine

Palmitic Acid

Octoxyglyceryl Behenate or Palmitate

Pelargonic Acid

Pentaerythrityl Stearate

Phosphatidylcholine

Potassium Laurate, Myristate, Oleate, Lauryl Hydroxypropyl Sulfonate,Cetyl Phosphate, Lauryl Sulfate, Palmate, Palmitate, Ricinoleate orStearate

Sodium Palmate, Palmitate, Phthalate Stearyl Amide, Ricinoleate,Stearate, Stearyl Sulfate, Trideceth Sulfate, Tridecyl Sulfate,Undecylenate, Lauroyl Lactylate, Lauryl Phosphate, Myristate, Oleate,Oleoyl Lactylate, Behenoyl Lactylate, Caproyl Lactylate, Caprylate,Isostearoyl Lactylate or Laurate

Propylene Glycol Behenate, Caprylate, Hydroxystearate, Isostearate,Laurate, Linoleate, Unolenate, Myristate, Oleate, Ricinoleate orStearate

Sorbitan Caprylate, Diisostearate, Dioleate, Distearate, Isostearate,Laurate, Oleate, Palmitate, Sesquiisostearate, Sesquioleate,Sesquistearate,

Stearate, Triisostearate, Trioleate or Tristearate

Raffinose Oleate

Stearic Acid

Stearoyl Lactylic Acid

Stearyl Alcohol

Sucrose Dilaurate, Distearate, Laurate, Myristate, Oleate, Palmitate,Polylaurate, Polylinoleate, Polyoleate, Polypalmate or Polystearate

C32˜C82 polyethylene glycol ether of behenyl alcohol

C20˜C106 polyethylene glycol ether of cetyl alcohol

C28˜C80 polyethylene glycol ether of cetyl or oleyl alcohol

C20˜C70 polyethylene glycol ether of cetyl and/or stearyl alcohol

C20˜C80 polyethylene glycol ether of cholesterol

C16˜C24 polyethylene glycol ether of decyl alcohol

C40˜C80 polyethylene glycol ether of dihydrocholesterol

C20˜C60 polyethylene glycol ether of isocetyl alcohol

C18˜C30 polyethylene glycol ether of isodecyl alcohol

C18˜C40 polyethylene glycol ether of isolauryl alcohol

C20˜C120 polyethylene glycol ether of isostearyl alcohol

C12˜C120 polyethylene glycol ether of glyceril caprate, caprylate,laurate, myristate, oleate, palmitate or stearate

C14˜C100 polyethylene glycol ether of lauryl alcohol

C16˜C24 polyethylene glycol ether of myristyl alcohol

C20˜C70 polyethylene glycol ether of oleyl alcohol

C10˜C100 polyethylene/polypropylene glycol ether of butyl alcohol

C20˜C106 polyethylene/polypropylene glycol ether of cetyl alcohol

C20˜C100 polyethylene/polypropylene glycol ether of decyl alcohol

C14˜C100 polyethylene/polypropylene glycol ether of lauryl alcohol

Carboxylic acid ester of C20˜C120 polyethylene glycol ether ofisostearyl alcohol

Carboxylic acid esters of C14˜C100 polyethylene glycol ether of laurylalcohol

Carboxylic acid ester of C16˜C24 polyethylene glycol ether of myristylalcohol

Citric acid diesters of C14˜C100 polyethylene glycol ether of laurylalcohol

Isopropyl Laurate, Myristate, Palmitate or Stearate

Lauric acid ester of C30˜C120 polyethylene glycol ether of sorbitol

Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate

Phosphoric acid ester of C20˜C106 polyethylene glycol ether of cetylalcohol

Phosphoric acid ester of C20˜C120 polyethylene glycol ether ofisostearyl alcohol

Phosphoric acid diesters of C14˜C100 polyethylene glycol ether of laurylalcohol

Phosphoric acid esters and/or diesters of C20˜C70 polyethylene glycolether of oleyl alcohol

Stearic acid ester of C15˜C30 polyethylene glycol ether of glycerin

Stearic acid ester of C20˜C60 polyethylene glycol ether of isocetylalcohol

Stearic acid ester of C20˜C120 polyethylene glycol ether of isostearylalcohol

Diethanolamine salt of phosphoric acid ester of C20˜C106 polyethyleneglycol ether of cetyl alcohol

Diethanolamine salt of phosphoric acid ester of C20˜C70 polyethyleneglycol ether of cetyl and/or stearyl alcohol

Diethanolamine salt of Phosphoric acid ester of C20˜C70 polyethyleneglycol ether of oleyl alcohol

Disodium salt of citric acid ester of C14˜C100 polyethylene glycol etherof lauryl alcohol

Disodium salt of phosphoric acid ester of C14˜C100 polyethylene glycolether of lauryl alcohol

Disodium salt of phosphoric acid ester of C20˜C70 polyethylene glycolether of oleyl alcohol

Monoethanolamine salt of phosphoric acid ester of C20˜C70 polyethyleneglycol ether of cetyl and/or stearyl alcohol

C12˜C120 polyethylene glycol diester of behenic, capric, caprylic,lauric, oleic, octanoic, palmitic or stearic acid

Polyesters of C6˜C40 polyglycerin and behenic, capric, caprylic, lauric,oleic, octanoic, palmitic or stearic acid.

The compositions of this invention may also include one or morematerials that may function as as an ultravilolet light absorber toprotect a product made from the composition from chemical or physicaldeterioration induced by ultraviolet light. UV absorbers, like sunscreenagents, have the ability to convert incident ultraviolet radiation intoless damaging infrared radiation (heat). Suitable materials that mayfunction as an ultraviolet light absorber include one or more of thefollowing:

Acetaminosalol

3-Benzylidene Camphor

Stilbenedisulfonate

Allantoin PABA

Disodium Distyrylbiphenyl Disulfonate

Benzalphthalide

Sulfonamide

Drometrizole

Benzophenone

Benzylidene Camphor Sulfonic Acid

Ethyl Dihydroxypropyl PABA

Benzophenone substituted with one or more groups selected from hydroxyl,alkoxy, alkyl, halogen and sulfonate

Benzyl Salicylate

Ethyl Diisopropylcinnamate, Methoxycinnamate or Urocanate

Bumetrizole

Ethyl PABA

Butyl Methoxydibenzoylmethane

Butyl PABA

Etocrylene

Cinoxate

Ferulic Acid

Glyceryl Octanoate Dimethoxycinnamate

Di-t-Butyl Hydroxybenzylidene Camphor

Glyceryl PABA

Digalloyl Trioleate

Glycol Salicylate

Diisopropyl Methyl Cinnamate

Isoamyl p-Methoxycinnamate

Disodium Bisethylphenyl Triaminotriazine

Isopropylbenzyl Salicylate

Isopropyl Dibenzoylmethane

Octyl Triazone

Sodium Urocanate

Isopropyl Methoxycinnamate

PABA

Menthyl Anthranilate or Salicylate

Pentyl Dimethyl PABA

Terephthaylidene Dicamphor Sulfonic Acid

4-Methylbenzylidene Camphor

Phenylbenzimidazole Sulfonic Acid

Titanium Dioxide

Octocrylene

Polyacrylamidomethyl Benzylidene Camphor

TriPABA Panthenol

Octrizole

Potassium Methoxycinnamate

Urocanic Acid

Octyl Dimethyl PABA

Potassium Phenylbenzimidazole Sulfonate

Octyl Methoxycinnamate or Salicylate

Sodium Phenylbenzimidazole Sulfonate

A formulated mixture of one or more carriers, adjuvants and/or additivesmay be selected from the members of the groups thereof contained in thelists set forth above. They may also be selected from a subgroup of themembers of the foregoing lists formed by omitting any one or moremembers from the whole groups as set forth in the above lists. As aresult, a mixture of carriers, adjuvants and/or additives may in suchinstance not only be made from one or more members selected from anysubgroup of any size that may be formed by all the various differentcombinations of individual members from the whole groups as set forth inthe above lists, but may also be made in the absence of members thathave been omitted from the whole groups to form the subgroup. Thesubgroup formed by omitting various members from the whole group in thelist above may, moreover, be an individual member of a whole group suchthat a carrier, adjuvant and/or additive is provided in the absence ofall other members of the whole groups except the selected individualmember.

Dihydronepetalactones may be utilized in the present inventionindividually or combined in any proportion. As is conventional in theart, the desired amount of an insect repellent composition to be addedto a given insect susceptible article with properties of insectrepellency is determined by the nature of the product and other factors.These factors include both considerations of cost and the nature of theother ingredients in the insect repellent composition or repellentarticle, their amounts, and the desired repellency effect. In general,the composition of the repellent should contain sufficient amounts ofactive insect repellant material to be efficacious in repelling theinsect from the host over a prolonged period of time (preferably, for aperiod of at least several hours).

The amount of each dihydronepetalactone of Formula I or mixtures thereofin an insect repellent composition or repellent article that containsone or more of the carriers, adjuvants and/or additives as describedabove will generally not exceed about 80% by weight based on the weightof the final product, however, greater amounts may be utilized incertain applications and this amount is not limiting. More preferably, asuitable amount of dihydronepetalactone will be at least about 0.001% byweight and preferably about 0.01% up to about 50% by weight; and morepreferably, from about 0.01% to about 20% weight percent, based on theweight of the composition or article. Specific compositions will dependon the intended use.

The dihydronepetalactone repellent compositions of the present inventioncan be formulated without a carrier and be effective. More often,however, the insect repellent composition will include a carrier andcontain about 0.001-50% weight of the disclosed compounds, and suchcompound is usually in intimate mixture with the carrier to bring theactive material into position for repelling common insect pests, such asbiting insects, wood-boring insects, noxious insects, household pests,and the like.

The compositions of the invention may be formulated and packaged so asto deliver the product in a variety of forms including as a solution,suspension, cream, ointment, gel, film or spray, depending on thepreferred method of use. The carrier may be an aerosol compositionadapted to disperse the dihydronepetalactone into the atmosphere bymeans of a compressed gas.

Desirable properties of a topical insect repellent article include lowtoxicity, resistance to loss by water immersion or sweating, low or noodor or at least a pleasant odor, ease of application, and rapidformation of a dry tack-free surface film on the host's skin. In orderto obtain these properties, the formulation for a topical insectrepellent article should permit insect-infested animals (e.g., dogs withfleas, poultry with lice, cows with ticks, and humans) to be treatedwith an insect repellent composition of the present invention bycontacting the skin, fur or feathers of such an animal with an effectiveamount of the repellent article for repelling the insect from the animalhost. Thus, dispersing the article into the air or dispersing thecomposition as a liquid mist or fine dust will permit the repellentcomposition to fall on the desired host surfaces. Likewise, directlyspreading of the liquid/semi-solid/solid repellent article on the hostis an effective method of contacting the surface of the host with aneffective amount of the repellent composition.

Embodiments of the present invention which may be used as a topicalinsect repellent articles, include (but are not limited to): colognes,lotions, sprays, creams, gels, ointments, bath and shower gels, foamproducts (e.g., shaving foams), makeup, deodorants, shampoo, hairlacquers/hair rinses, and personal soap compositions (e.g., hand soapsand bath/shower soaps).

This invention also relates to the use of dihydronepetalactone mixturesas insect repellents in a variety of articles which are susceptible toattack by insects. These outdoor consumable products will generally, butnot necessarily, comprise an insect repellent composition of theinvention, but will contain an effective amount of dihydronepetalactone.Typical articles that can be improved by the use ofdihydronepetalactones and mixtures thereof include, but are not limitedto: air fresheners, candles, other scented articles, fibers, sheets,cloth [e.g., for clothing, nettings (mosquito netting), and otherfabrics], paper, paint, ink, clay, woods, furniture (e.g., for patiosand decks), carpets, sanitary goods, plastics, polymers, and the like.

The dihydronepetalactone compositions of this invention may be blendedwith polymers, which may also involve a controlled release systems.Compatible polymers may or may not be biodegradable. Exemplary polymersare high density polyethylene or low density polyethylene, biodegradablethermoplastic polyurethanes, biodegradable ethylene polymers, andpoly(epsilon caprolactone) homopolymers and compositions containing thesame as disclosed in U.S. Pat. No. 4,496,467, U.S. Pat. No. 4,469,613and U.S. Pat. No. 4,548,764.

Dihydronepetalactones are particularly advantageous for use as repellentmaterials in preparations of the present invention for a variety ofreasons.

First, the compounds are cost effective to produce, an importantconsumer consideration when choosing an effective repellent. Manycommercially available repellent products are only effective inrelatively concentrated form, including as much as 5-30% (or more)repellent in a carrier, based on total weight. U.S. Pat. No. 4,416,881to McGovern et al., for example, discloses repellent concentrations of6.25-25% repellent in a carrier.

Secondly, the compounds are known natural compounds, thus overcomingconcerns raised against synthetic chemicals such as DEET as the primaryactive ingredient in repellent compositions.

Finally, in addition to the natural repellent properties of thedihydronepetalactone mixtures thus prepared, the compositions alsopossess a unique and pleasant fragrance. The fragrance notes of thesubject compounds make them useful in imparting, altering, augmenting orenhancing the overall olfactory component of an insect repellentcomposition or article, for example, by utilizing or moderating theolfactory reaction contributed by one or more other ingredients in thecomposition. Specifically, the dihydronepetalactones of the invention ormixtures thereof may be utilized to either mask or modify the odorcontributed by other ingredients in the formulation of the finalrepellent composition or article, and/or to enhance consumer appeal of aproduct by imparting a characteristic perfume or aroma. It is expectedthat the pleasant fragrance of dihydronepetalactones will possess muchgreater appeal to consumers than other insect repellent compounds,particularly DEET.

Dihydronepetalactones and their uses are also described in U.S. Ser. No.10/349,865, filed Jan. 23, 2003, which is incorporated in its entiretyas a part hereof for all purposes.

Where the composition of this invention is stated or described ascomprising, including, containing, having, being composed of or beingconstituted by certain components, it is to be understood, unless thestatement or description explicitly provides to the contrary, that oneor more components in addition to those explicitly stated or describedmay be present in the composition. In an alternative embodiment,however, the composition of this invention may be stated or described asconsisting essentially of certain components, in which embodimentcomponents that would materially alter the principle of operation or thedistinguishing characteristics of the composition are not presenttherein. In a further alternative embodiment, the composition of thisinvention may be stated or described as consisting of certaincomponents, in which embodiment components other than impurities are notpresent therein.

Where the indefinite article “a” or “an” is used with respect to astatement or description of the presence of a component in thecomposition of this invention, it is to be understood, unless thestatement or description explicitly provides to the contrary, that theuse of such indefinite article does not limit the presence of thecomponent in the composition to one in number.

What is claimed is:
 1. An insect repellent composition comprising (a) adihydronepetalactone, or a mixture of dihydronepetalactonestereoisomers, represented by the general formula:

(b) an alcohol selected from a (i) C₆˜C₂₀ linear, branched or cyclicalkanol and (ii) a C₁₀˜C₅₀ alcohol, and (c) an ester.
 2. A compositionaccording to claim 1 further comprising a C₆˜C₂₀ linear, branched orcyclic alkane polyol.
 3. A composition according to claim 1 furthercomprising a C₄˜C₄₀₀ polyethylene glycol.
 4. A composition according toclaim 1 further comprising a C₄˜C₄₀₀ polyethylene ether glycol.
 5. Acomposition according to claim 1 further comprising a C₁₆˜C₁₄₀polyethylene glycol ether of a C₁₂˜C₆₀ alcohol.
 6. A compositionaccording to claim 1 further comprising a paraben.
 7. A compositionaccording to claim 6 wherein the paraben is selected from the groupconsisting of methylparaben, ethylparaben, propylparaben,isopropylparaben, butylparaben, isobutylparaben, isodecylparaben,benzylparaben and phenylparaben.
 8. A composition according to claim 1further comprising water.
 9. A composition according to claim 1 whereinthe ester comprises an ester of a C₁₂˜C₄₀ carboxylic acid and a C₈˜C₄₀polyethylene glycol.
 10. A composition according to claim 1 wherein theester is selected from the group consisting of (a) Amyl, Methyl, Butyl,Ethyl, Ethoxyethanol, Ethoxydiglycol, Tetrahydrofurfuryl, Isoamyl,Isobutyl, Isopropyl or Propyl Acetate; (b) Isobutyl, Methyl, Stearyl,Octyl, Lauryl, Myristyl or Palmitoyl Benzoate; (c) Dimethyl Phthalate,Glutarate, Maleate, Adipate or Succinate; (d) Octyl, Lauryl, Myristyl,Palmitoyl or Stearyl Salicylate; (e) Glycol Oleate, Palmitate, Stearateor Ricinoleate; (f) Butyl Isostearate, Myristate or Oleate; (g) CetylAcetate, Caprylate, Lactate, Laurate, Octanoate or Oleate; (h)Isostearyl Benzoate, Lactate, Neopentanoate, Octanoate, Palmitate orMyristate; (i) Isoamyl Laurate; (j) Isobutyl Myristate, Palmitate,Pelargonate or Stearate; (k) Isocetyl Isodecanoate, Palmitate orStearate; (L) Isodecyl Citrate, Hydroxystearate, Laurate, Myristate,Neopentanoate, Palmitate or Stearate; (m) Isopropyl Hydroxystearate,Isostearate, Lanolate, Laurate, Linoleate, Myristate, Oleate, Palmitateor Stearate; (n) Methyl Hydroxystearate, Laurate, Isostearate,Myristate, Oleate, Palmitate, Stearate or Pelargonate; (o) PolyglycerylMyristate, Oleate, Pentastearate or Ricinoleate; (p) Stearyl Acetate,Benzoate or Lactate; (q) Phosphoric acid esters and diesters of C₁₆˜C₁₄₀polyethylene glycol ether of C₁₂˜C₆₀ alcohols; (r) Glyceryl Caprylate,Caprate, Hydroxystearate, Isopalmitate, Isostearate, Lanolate, Laurate,Oleate, Linoleate, Linolenate, Myristate, Palmitate, Stearate orRicinoleate; and (s) Propylene Glycol Hydroxystearate, Isostearate,Stearate, Laurate, Linoleate, Myristate, Ricinoleate, Oleate orCaprylate.
 11. A composition according to claim 1 formulated as aliquid.
 12. A composition according to claim 1 formulated as a lotion.